CN102580081B - NAD (Nicotinamide Adenine Dinucleotide), aluminum hydroxide compound adjuvant and vaccine containing compound adjuvant - Google Patents
NAD (Nicotinamide Adenine Dinucleotide), aluminum hydroxide compound adjuvant and vaccine containing compound adjuvant Download PDFInfo
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- CN102580081B CN102580081B CN201210040896.7A CN201210040896A CN102580081B CN 102580081 B CN102580081 B CN 102580081B CN 201210040896 A CN201210040896 A CN 201210040896A CN 102580081 B CN102580081 B CN 102580081B
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Abstract
The invention provides NAD (Nicotinamide Adenine Dinucleotide), an aluminum hydroxide compound adjuvant and a vaccine containing the compound adjuvant. The compound adjuvant consists of NAD and aluminum hydroxide in the mass ratio of (1-5):(50-100). The vaccine containing the compound adjuvant is obtained by adding 0.51-1.05mg of compound adjuvant into every 100 muL of antigen liquid. The compound adjuvant provided by the invention has the advantages of readily-available raw materials, simple preparation process, low cost and stability, and can be taken as an adjuvant of a hepatitis B vaccine, a protein vaccine, a virus vaccine and the like. Due to the combined application of the compound adjuvant and the vaccine, the immune response of a vaccine fluid can be enhanced effectively, and the enhancing effect is superior to those of a single NAD adjuvant and an aluminum hydroxide adjuvant; and moreover, the compound adjuvant and the vaccine are nontoxic, free from side effects and safe and reliable for using in an immune dosage range.
Description
Technical field
The present invention relates to a kind of composite adjuvant, be specifically related to the composite adjuvant of a kind of nicotinamide adenine dinucleotide and aluminium hydroxide, belong to immunological technique field.
Background technology
In recent years, along with deepening continuously of immunology research and developing rapidly of technique for gene engineering, the research of the new generation vaccines such as live vector vaccine, DNA vaccination and protein vaccine makes encouraging progress.These new generation vaccine purity are high, high specificity, but a little less than immunogenicity, and induction immune response is strong not, therefore apply adjuvant and strengthen its immunogenicity or strengthen host antigen immune response is just seemed to particularly important.
People, in finding novel adjuvant, also pay attention to more to the Upgrading of conventional adjuvant.Though emerged in large numbers many novel adjuvants, all in the experimental study stage.At present in vaccine industry aluminium adjuvant be the most traditional, most important be also the maximum vaccine adjuvant of application.
The mechanism of action of aluminium adjuvant is mainly in tissue, to form antigen storage to produce particulate antigen, promotes antigen presentation to immunocyte, and antigen is detained, and slowly discharges, thereby attracts active lymphocyte, activating complement system.But as vaccine adjuvant, its targeting exists defect, can not cause that the specific cellular immunity of body should react.And some other material that confirms adjuvant effect just under study for action, due to safety, effectiveness or economic aspect problem, fails to be approved for human body.
Nicotinamide adenine dinucleotide (NAD) is the important coenzyme of one in bio-metabolic process, and its structural formula is (Fig. 1) as shown in the figure.Its basic physiological function is the metabolism of the growth, differentiation and the energy that maintain cell, not only intracellular redox state is had to important regulating action, and be often used as intravital metabolic index, have extremely closely and contact with great life processes such as the metabolism of cell, the rhythm and pace of moving things, aging, pathological changes, death.Friedrich Haag confirms that NAD is a kind of cell endogenous danger signal.It can be used as the immune modulatory molecules of T cell simultaneously, induction muroid CD4
+and CD8
+the apoptosis of T cell, but whether it has adjuvant effect and is still not clear.
Summary of the invention
There is toxic and side effects, the problem such as expensive for solving existing vaccine adjuvant, the invention provides the composite adjuvant of a kind of safe, effective, stable, cheap nicotinamide adenine dinucleotide and aluminium hydroxide.
The present invention also provides a kind of vaccine of the composite adjuvant that contains nicotinamide adenine dinucleotide and aluminium hydroxide.
The present invention is to provide so a kind of NAD, aluminium hydroxide composite adjuvant, it is characterized in that being formed by the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=1～5 ︰ 50～100.
Described nicotinamide adenine dinucleotide is commercial curable product, and molecular formula is C
21h
26n
7o
14p
2, molecular weight is 663.4177, as shown in Figure 1, the recommended dose in human body is 10～50 μ g to structural formula.
Described aluminium hydroxide is current conventional alumine hydroxide colloid adjuvant, its method for making reference " Chinese Pharmacopoeia (three) ", (Chinese Pharmacopoeia Commission. Beijing: People's Health Publisher .2005:118-119), the dosage in human body is 1.8～2.7 mg.
The present invention is to provide a kind of like this vaccine that contains composite adjuvant, it is characterized in that adding the composite adjuvant of 0.51～1.05mg in every 100 μ L antigen liquids, and composite adjuvant is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=1～5 ︰ 50～100.
Described antigen liquid is in every 100 μ L normal saline, and miscible have 2 μ g antigens.
Described antigen is conventional hepatitis B surface antigen.
The immunoreation of the composite adjuvant induction of nicotinamide adenine dinucleotide and aluminium hydroxide is humoral immune reaction.
The present invention compared with prior art has following advantages and effect: (1) this composite adjuvant is without toxicity, side effect, not accumulation toxicity, and it is safe and reliable within the scope of immunizing dose, using; (2) the effectively humoral immunoresponse(HI) of inducing antigen-specific of this composite adjuvant, and its humoral immunoresponse(HI) effect of inducing is better than single aluminium adjuvant and single nicotinamide adenine dinucleotide; (3) this composite adjuvant raw material is easy to get, and is commercially available prod, and preparation technology is simple, and cost is low, and stable performance can be used as the adjuvants such as Hepatitis B virus vaccine, protein vaccine and viral vaccine; (4) this composite adjuvant can effectively strengthen vaccine humoral immunoresponse(HI) with vaccine use in conjunction, and reinforced effects is better than single nicotinamide adenine dinucleotide adjuvant and single aluminum hydroxide adjuvant.
Brief description of the drawings
Fig. 1 is nicotinamide adenine dinucleotide molecular structural formula;
Fig. 2 is for using after the composite adjuvant that provides of embodiment 1, in 14 weeks, and the anti-HBsIgG antibody horizontal of each experimental mice serum;
Fig. 3 is for using after the composite adjuvant that provides of embodiment 2, in 14 weeks, and the anti-HBsIgG antibody horizontal of each experimental mice serum;
Fig. 4 is for using after the composite adjuvant that provides of embodiment 3, in 14 weeks, and the anti-HBsIgG antibody horizontal of each experimental mice serum;
Fig. 5 is for using after the composite adjuvant that provides of embodiment 4, in 14 weeks, and the anti-HBsIgG antibody horizontal of each experimental mice serum.
Detailed description of the invention
Below in conjunction with embodiment, further set forth the present invention.These embodiment are only not used in and limit the scope of the invention for the present invention is described, the experimental technique of unreceipted actual conditions in the following example, the condition of advising according to normal condition or according to manufacturer.The use that better condition implementation method described in literary composition only presents a demonstration.
Composite adjuvant provided by the invention is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=1 ︰ 100.
The vaccine that contains composite adjuvant provided by the invention is: in every 100 μ L antigen liquids, add the composite adjuvant of 1.01mg to mix, wherein, composite adjuvant is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=1 ︰ 100, antigen liquid is in every 100 μ L normal saline, miscible have 2 μ g antigens, this antigen is conventional hepatitis B surface antigen, purchased from Shenzhen safe biological product company limited, nicotinamide adenine dinucleotide NAD is purchased from upper sea base rice bio tech ltd, aluminium hydroxide is conventional alumine hydroxide colloid adjuvant, its method for making is with reference to " Chinese Pharmacopoeia (three) ", (Chinese Pharmacopoeia Commission. Beijing: People's Health Publisher .2005:118-119).
Immunity test and the effect of the present embodiment 1 gained hepatitis B surface antigen are as follows:
A, immunity
By ICR mice be divided into composite adjuvant group, the single adjuvant group of aluminium hydroxide, without adjuvant group and blank group, totally five groups, 25 every group.The vaccine cumulative volume that contains composite adjuvant of injection embodiment 1 is 100 μ L, in leg muscle is expelled to Mice Body.
The single adjuvant group of aluminium hydroxide is by miscible in 100 μ L normal saline to aluminium hydroxide 1mg and hepatitis B surface antigen 2 μ g, then in leg muscle is expelled to Mice Body.
That hepatitis B surface antigen 2 μ g are dissolved in 100 μ L normal saline without adjuvant group, then in leg muscle is expelled to Mice Body.
Blank group is to every injected in mice 100 μ L normal saline.
Immunization protocol: through leg muscle immune mouse, immune time was for once at the 0th week.
B, ELISA detect the anti-HBsIgG level of serum
Latter the 4th, 6,8,10,12,14 weeks of immunity in the 0th week, gather mouse tail vein blood, separation of serum, ELISA detects the anti-HBs IgG of serum level, detect by albumen micropore kit method, concrete grammar is: 40 μ l HBsAg are dissolved in 10ml 1 × coated diluent, mix, coated 96 hole ELISA Plate, 100 μ l/ holes; ELISA Plate is put in wet box, spends the night at 4 DEG C; Outwell liquid in hole, clap clean plank; Add 1 × BSA, 200 μ l/ holes, ELISA Plate is placed 1h at 37 DEG C of wet boxes; Outwell liquid in hole, clap clean plank; Serum, after doubling dilution, adds ELISA Plate, 100 μ l/ holes, and 37 DEG C of wet boxes are placed 1h; Wash plate 4 times by the washing liquid of test kit preparation, each 5min, last is clapped clean ELISA Plate; Add two of test kit preparation to resist, 100 μ l/ holes, 37 DEG C of wet boxes are placed 1h; Wash plate 4 times by washing liquid, each 5min, last is clapped clean ELISA Plate; Add the nitrite ion of test kit preparation, 100 μ l/ holes, lucifuge colour developing 10～25min; Add stop buffer, every hole 100 μ l; ELISA Plate is put into microplate reader, reads plate at 405nm place.
C, data analysis
Obtained experimental data is carried out to one factor analysis of variance with SPSS11.5 statistical software, the statistical significance taking P ﹤ 0.05 as difference.
Table 1 is for using after the composite adjuvant that provides of embodiment 1, in 14 weeks, and the anti-HBsIgG antibody horizontal of each experimental mice serum (OD value).
Table 1
Can find out by data analysis, since the 4th week, each experimental group can produce anti-HBsIgG antibody, and generally reached peak value in the 8th week, wherein obtained immune effect the best of composite adjuvant group, within 14 weeks, antibody is all significantly higher than without Adjuvanted vaccines group, P < 0.05, and can between detection period, maintain higher level.The experimental group of all interpolation adjuvants produces antibody horizontal and is all significantly higher than without Adjuvanted vaccines group, wherein composite adjuvant group antibody horizontal is significantly higher than the single adjuvant group of NAD and aluminum hydroxide adjuvant group, P < 0.05, prompting nicotinamide adenine dinucleotide and aluminium hydroxide composite adjuvant can strengthen the immune effect effect of hepatitis B surface antigen, and its humoral immunization reinforced effects is mono-higher than aluminium adjuvant and NAD
One adjuvant, as shown in Figure 2 in 14 weeks, the anti-HBsIgG antibody horizontal of each experimental mice serum.
Embodiment 2
Composite adjuvant provided by the invention is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=5 ︰ 100.
The vaccine that contains composite adjuvant provided by the invention is: in the antigen liquid of 100 μ L, add the composite adjuvant of 1.05mg to mix, wherein, composite adjuvant is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=5 ︰ 100, antigen liquid is in every 100 μ L normal saline, miscible have 2 μ g antigens, and all the other are with embodiment 1.
Immunity test and the effect of the present embodiment 2 gained hepatitis B surface antigens are as follows:
A, immunity
With embodiment 1
Only, composite adjuvant group is that the composite adjuvant 1.05mg of above-mentioned gained nicotinamide adenine dinucleotide and aluminium hydroxide and hepatitis B surface antigen 2 μ g are melted in 100 μ L normal saline, then in leg muscle is expelled to Mice Body.
B, ELISA detect the anti-HBsIgG level of serum
With embodiment 1
C, data analysis
Obtained experimental data is carried out to one factor analysis of variance with SPSS11.5 statistical software, the statistical significance taking P ﹤ 0.05 as difference.
Table 2 is for using after the composite adjuvant that provides of embodiment 2, in 14 weeks, and the anti-HBsIgG antibody horizontal of each experimental mice serum (OD value).
Table 2
Can find out by data analysis, since the 4th week, each experimental group can produce anti-HBsIgG antibody, and generally reached peak value in the 8th week, wherein obtained immune effect the best of composite adjuvant group, within 14 weeks, antibody is all significantly higher than without Adjuvanted vaccines group, P < 0.05, and can between detection period, maintain higher level.The antibody horizontal that the experimental group of all interpolation adjuvants all produces is significantly higher than without Adjuvanted vaccines group, and wherein composite adjuvant group antibody horizontal is significantly higher than the single adjuvant group of NAD and aluminum hydroxide adjuvant group, P < 0.05.Prompting nicotinamide adenine dinucleotide and aluminium hydroxide composite adjuvant can strengthen the immune effect effect of hepatitis B surface antigen, its humoral immunization reinforced effects is higher than aluminium adjuvant and the single adjuvant of NAD, as shown in Figure 3 in 14 weeks, the anti-HBsIgG antibody horizontal of each experimental mice serum.
Composite adjuvant provided by the invention is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=1 ︰ 50.
The vaccine that contains composite adjuvant provided by the invention is: in the antigen liquid of every 100 μ L, add the composite adjuvant of 0.51mg to mix, wherein, composite adjuvant is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=1 ︰ 50, antigen liquid is in every 100 μ L normal saline, miscible have 2 μ g antigens, and all the other are with embodiment 1.
Immunity test and the effect of the present embodiment gained hepatitis B surface antigen are as follows:
A, immunity
With embodiment 1
Only, composite adjuvant group is that the composite adjuvant 0.51mg of above-mentioned gained nicotinamide adenine dinucleotide and aluminium hydroxide and hepatitis B surface antigen 2 μ g are melted in 100 μ L normal saline, then in leg muscle is expelled to Mice Body.
B, ELISA detect the anti-HBsIgG level of serum
With embodiment 1
C, data analysis
Obtained experimental data is carried out to one factor analysis of variance with SPSS11.5 statistical software, the statistical significance taking P ﹤ 0.05 as difference.
Table 3 is for using after the composite adjuvant that provides of embodiment 3, in 14 weeks, and the anti-HBsIgG antibody horizontal of each experimental mice serum.
Table 3
Can find out by data analysis, since the 4th week, each experimental group can produce anti-HBsIgG antibody, and generally reached peak value in the 8th week, wherein obtained immune effect the best of composite adjuvant group, within 14 weeks, antibody is all significantly higher than without Adjuvanted vaccines group, P < 0.05, and can between detection period, maintain higher level.The antibody horizontal that the experimental group of all interpolation adjuvants all produces is significantly higher than without Adjuvanted vaccines group, and wherein composite adjuvant group antibody horizontal is significantly higher than the single adjuvant group of NAD and aluminum hydroxide adjuvant group, P < 0.05.Prompting nicotinamide adenine dinucleotide and aluminium hydroxide composite adjuvant can strengthen the immune effect of hepatitis B surface antigen, its humoral immunization reinforced effects is higher than aluminium adjuvant and the single adjuvant of NAD, as shown in Figure 4 in 14 weeks, the anti-HBsIgG antibody horizontal of each experimental mice serum.
Embodiment 4
Composite adjuvant provided by the invention is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=5 ︰ 50.
The vaccine that contains composite adjuvant provided by the invention is: in the antigen liquid of every 100 μ L, add the composite adjuvant of 0.55mg to mix, wherein, composite adjuvant is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=5 ︰ 50, antigen liquid is in every 100 μ L normal saline, miscible have 2 μ g antigens, and all the other are with embodiment 1.
Immunity test and the effect of the present embodiment gained hepatitis B surface antigen are as follows:
A, immunity
With embodiment 1
Only, composite adjuvant group is that the composite adjuvant 0.55mg of above-mentioned gained nicotinamide adenine dinucleotide and aluminium hydroxide and hepatitis B surface antigen 2 μ g are melted in 100 μ L normal saline, then in leg muscle is expelled to Mice Body.
B, ELISA detect the anti-HBsIgG level of serum
With embodiment 1
C, data analysis
Obtained experimental data is carried out to one factor analysis of variance with SPSS11.5 statistical software, the statistical significance taking P ﹤ 0.05 as difference.
Table 4 is for using after the composite adjuvant that provides of embodiment 4, in 14 weeks, and the anti-HBsIgG antibody horizontal of each experimental mice serum.
Table 4
Can find out by data analysis, since the 4th week, each experimental group can produce anti-HBsIgG antibody, and generally reached peak value in the 8th week, wherein obtained immune effect the best of composite adjuvant group, within 14 weeks, antibody is all significantly higher than without Adjuvanted vaccines group, P < 0.05, and can between detection period, maintain higher level.The antibody horizontal that the experimental group of all interpolation adjuvants all produces is significantly higher than the antibody horizontal without Adjuvanted vaccines group, and wherein composite adjuvant group antibody horizontal is all significantly higher than the single adjuvant group of NAD and aluminum hydroxide adjuvant group P < 0.05.Prompting nicotinamide adenine dinucleotide and aluminium hydroxide composite adjuvant can strengthen the immune effect effect of hepatitis B surface antigen, its humoral immunization reinforced effects is higher than aluminium adjuvant and the single adjuvant of NAD, as shown in Figure 5 in 14 weeks, the anti-HBsIgG antibody horizontal of each experimental mice serum.
Claims (3)
1. a Hepatitis B virus vaccine that contains NAD, aluminium hydroxide composite adjuvant, the composite adjuvant that it is characterized in that adding 0.51～1.05mg in every 100 μ L hepatitis B antigen liquid, described composite adjuvant is made up of the component of following mass ratio: Yan amide adenine Er He Gan Suan ︰ aluminium hydroxide=1～5 ︰ 50～100; Described antigen liquid is in every 100 μ L normal saline, and miscible have 2 μ g antigens, and this antigen is conventional hepatitis B surface antigen.
2. the Hepatitis B virus vaccine that contains NAD, aluminium hydroxide composite adjuvant according to claim 1, is characterized in that: described aluminium hydroxide is conventional aluminum hydroxide adjuvant.
3. the Hepatitis B virus vaccine that contains NAD, aluminium hydroxide composite adjuvant according to claim 1, is characterized in that: described nicotinamide adenine dinucleotide is commercial curable product, molecular formula is C
21h
26n
7o
14p
2, molecular weight is 663.4177.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1030019A (en) * | 1986-09-22 | 1989-01-04 | 埃默里大学 | Vaccine and preparation method thereof |
| CN1060027A (en) * | 1990-06-27 | 1992-04-08 | 埃默里大学 | improved adjuvant and vaccine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1030019A (en) * | 1986-09-22 | 1989-01-04 | 埃默里大学 | Vaccine and preparation method thereof |
| CN1060027A (en) * | 1990-06-27 | 1992-04-08 | 埃默里大学 | improved adjuvant and vaccine |
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| LUND，Frances E..ID7210988.《RePORTER_PRJABS_C_FY2007》.2010, * |
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